Alzheimer’s pathology is associated with altered cognition, brain volume, and plasma biomarker patterns in traumatic encephalopathy syndrome

Background Traumatic encephalopathy syndrome (TES) is a clinical phenotype sensitive but non-specific to underlying chronic traumatic encephalopathy (CTE) neuropathology. However, cognitive symptoms of TES overlap with Alzheimer’s disease (AD), and features of AD pathology like beta-amyloid (Aβ) plaques often co-occur with CTE, making clinical-to-pathological conclusions of TES diagnoses challenging. We investigated how Alzheimer’s neuropathological changes associated with cognition, brain volume, and plasma biomarkers in patients with repetitive head impacts (RHI)/TES, clinical AD, or typically aging controls. Methods We studied 154 participants including 33 with RHI/TES (age 61.5 ± 11.5, 100% male, 11/33 Aβ[ +]), 62 with AD and no known prior RHI (age 67.1 ± 10.2, 48% male, 62/62 Aβ[ +]), and 59 healthy controls without RHI (HC; age 73.0 ± 6.2, 40% male, 0/59 Aβ[ +]). Patients completed neuropsychological testing (memory, executive functioning, language, visuospatial) and structural MRI (voxel-based morphometry analysis), and provided plasma samples analyzed for GFAP, NfL, IL-6, IFN-γ, and YKL-40. For cognition and plasma biomarkers, patients with RHI/TES were stratified as Aβ[ +] or Aβ[ −] and compared to each other plus the AD and HC groups (ANCOVA adjusting for age and sex). Differences with at least a medium effect size (Cohen’s d > 0.50) were interpreted as potentially meaningful. Results Cognitively, within the TES group, Aβ[ +] RHI/TES performed worse than Aβ[-] RHI/TES on visuospatial (p = .04, d = 0.86) and memory testing (p = .07, d = 0.74). Comparing voxel-wise brain volume, both Aβ[ +] and Aβ[ −] RHI/TES had lower medial and anterior temporal lobe volume than HC and did not significantly differ from AD. Comparing plasma biomarkers, Aβ[ +] RHI/TES had higher plasma GFAP than HC (p = .01, d = 0.88) and did not significantly differ from AD. Conversely, Aβ[ −] RHI/TES had higher NfL than HC (p = .004, d = 0.93) and higher IL-6 than all other groups (p’s ≤ .004, d’s > 1.0). Conclusions Presence of Alzheimer’s pathology in patients with RHI/TES is associated with altered cognitive and biomarker profiles. Patients with RHI/TES and positive Aβ-PET have cognitive and plasma biomarker changes that are more like patients with AD than patients with Aβ[ −] RHI/TES. Measuring well-validated Alzheimer’s biomarkers in patients with RHI/TES could improve interpretation of research findings and heighten precision in clinical management. Supplementary Information The online version contains supplementary material available at 10.1186/s13195-023-01275-w.


PET Neuroimaging
Participants were scanned on one of two scanners: a Siemens Biograph 6 PET/CT scanner or ECAT PET scanner at the Lawrence Berkeley National Laboratory. Attenuation correction was performed using either an emission scan (ECAT) or low-dose CT scan (Biograph). PET acquisition and processing procedures are also detailed elsewhere [4]. four 5-min frames between 50-70min post injection. PIB scans were reconstructed using an ordered subset expectation maximum algorithm with weighted attenuation and were smoothed using a 4 mm Gaussian kernel with scatter correction (calculated image resolution 6.5 × 6.5 × 7.25 mm using Hoffman phantom). FBP scan reconstruction followed ADNI protocols (http://adni.loni.usc.edu/methods/).
Reconstructed PET frames were realigned for motion correction and coregistered with reslicing to participants' T1-weighted MRIs. Mean count images were converted into voxel-wise Standardized Uptake Value Ratio (SUVR) images (FBP-PET and PIB-PET, 50-70min; FTP-PET, 80-100min) using tracer specific reference regions defined using Freesurfer-derived MRI parcellation and the SUIT atlas, as previously defined [5]. Tracer specific reference regions were whole cerebellum for FBP, cerebellar gray matter for PIB, and inferior cerebellar gray matter for FTP. PET images were warped to MNI space with the MRI-based transformations. Finally, PET images were differentially smoothed to obtain about the same final resolution (i.e., about 8 mm 3 isotropic).
FBP-PET and PIB-PET SUVR images were centrally read as positive or negative at UCSF based on visual assessment [6]. SUVRs were then converted to Centiloids (CLs) scale to harmonize data across the two tracers [7][8][9]. A value of 100 CLs corresponds with the average degree of amyloid deposition observed in patients diagnosed with Alzheimer's disease dementia [10].
Tau-PET was performed using [18F]Flortaucipir (FTP; injected dose: ~10mCi; N=78). FTP-PET scan acquisition varied in their timing, although always including the 80-100min post injection window. FTP images were reconstructed using an ordered subset expectation maximum algorithm with weighted attenuation and were smoothed using a 4 mm Gaussian kernel with scatter correction (calculated image resolution 6.5 × 6.5 × 7.25 mm using Hoffman phantom). To quantify Flortaucipir binding, we extracted SUVR values from the whole cortex. An overall cortical SUVR was calculated with FTP-PET positivity defined as SUVR>1.27 [11].

Neuropathological Assessment
Two patients with TES had their beta-amyloid status determined via autopsy (1.1 and 7.7 year intervals between antemortem assessment and autopsy) using standardized sampling and staining protocols in the UCSF Neurodegenerative Disease Brain Brank as described elsewhere [12,13]. Sampling procedures followed recommended guidelines for CTE, AD, FTLD, and synucleinopathies classification [14][15][16]. AD burden (Aβ plaques and AD tau tangles) was defined as "None," "Low," "Moderate," or "High" AD neuropathologic changes (ADNC) based on current NIA-AA criteria [16]. Both of these patients had frequent neuritic and diffuse plaques (CERAD A2/C3 and A3/C3; Braak stage not considered due to reliance on Aβ-PET only for patients characterized during life). One additional patient with TES underwent autopsy, which confirmed antemortem Aβ-PET positivity status (4.2 year interval; CERAD A3/C3). Relevant to the convenience sample of 12 patients with TES who were evaluated at autopsy, CTE severity was defined according to McKee staging criteria [17] and as "High" or "Low" based on recently proposed classification methods that account for the number of brain regions with CTE-tau deposition (regardless of burden/density) [14]. Brains that were considered free of CTE pathology during initial autopsy evaluation were reexamined with additional regions reviewed for CTE tau pathology, per recent consensus group recommendations [14].